7-cyano androstane compounds



United rates patent This invention relates to a new method for preparing the novel 7-cyano-androstanes of the following general formulas:

CH3 CH3 in which A is an arrangement selected from the group consisting of and O CN' =0 and wherein R is an acyl radical derived from a hydrocarbon carboxylic acid having up to about 12 carbon atoms and R is an aliphatic hydrocarbon radical selected from the group of lower alkyl, alkenyl and alkynyl radicals; Y is an arrangement selected from the group consisting of H OH "H 'H and =0; X is hydrogen when Y is 'H and is selected from the group consisting of hydrogen and fluorine, when is a member of its group other than '11 Z represents the linkage between 0-1 and C-2 selected from the group consisting of single and double bond, and --CN is selected from the group consisting of 7ot-cyano and 7B-cyano.

Where the wavy line (i) is used in this application, it represents a generic expression for the aand B-steric configurations of substituents at C7 of the respective steroid molecule.

Among the 7(a and B)-cyano-androstane derivatives represented by the second of the above general formulas, as new compounds according to the invention, there are mentioned 7(a or [3)-cyano-A -androstene-3,l7-dione and 7(11 or fi)-cyano-testosterone as well as their Not-alkyl, alkenyl, and alkynyl-derivatives, their 11-keto-, llfi-hydroxy-, 9u-fluoro-11-ketoand 9oc-flUO1O-11B-hYd1OXY- derivatives, and furthermore the l-dehydro derivatives and the 17-esters of all of the aforementioned compounds; the first of the above formulas represents the 19-nor analogs of all of the above A -compounds.

Acyl groups R at 0-17 are derived from any carboxylic acid of 1 to about 12 carbon atoms, saturated or unsaturated, of straight, branched, cyclic or mixed cyclic-aliphatic chain, with or without functional substituents such as hydroxyl, acyloxy (of 1 to 12 carbon atoms), alkoxy (of 1 to carbon atoms) or halogen, such as chlorine or fluorine; typical for such esters of the 7-cyano-testosterones are, among others, the acetate, propionate, t-butylacetate, hemisuccinate, enanthate, caproate, benzoate, trimethylacetate, phenoxyacetate, cyclopentylpropionate and ,G-chloropropionate; the radical R at C-l7a may be an alkyl radical of up to 5 carbon atoms, such as methyl or ethyl, an alkenyl radical, such as vinyl or propenyl, or an alkynyl radical, such as, for example, ethynyl or propynyl.

Specific compounds pertaining to the novel steroidal derivatives according to the invention are beside those already mentioned the 7ocand 7fl-cyano derivatives of 17a-methyl-testosterone, 17ot-ethyl-testosterone, 17a-vinyltestosterone, 17a-propen(1-)yl-testosterone, 17a-ethynyltestosterone, 17a-propyn(l-)yl-testerone, as well as all of the aforementioned compounds having a keto or B-hydroxyl group at 011, or a keto group or fl-hydroxyl group at 011 together with a fluorine atom at 0904; the 70:- and 7fi-cyano derivatives of 19-nor-testosterone, 17amethyl-l9-nor-testosterone, 17a-ethyl-19-nor-testosterone, 17a-vinyl-19-nor-testosterone, 17ot-propen( 1-) yl-19-nortestosterone, 17a-ethynyl-l9-nor-testosterone, 17a-propyn- 1-) yl-19-nor-testosterone, 19-nor-A -andr0stene-3, 1 7-dione, as well as the aforementioned compounds having a keto or B-hydroxyl group at 0-11, the ll-(keto or B-hydroxyl)-19-n0r-testosterones, which may be optionally fluorinated at C-9e and which may have a hydrogen atom or a methyl group at C-l7a.

The new compounds which are the object of the pres-v ent invention, having an alkyl or alkenyl group at C-17u are anabolic hormones of the androgenic type which show a favorable anabolic-androgenic ratio and exhibit antigonadotrophic activity; the 17a-alkynyl-test-osterones are potent progestational agents.

The novel compounds according to the present invention can be produced by a process which is illustrated by the Reaction Diagram I shown below and essentially involvcs the introduction of the cyano group at C-7 into the 6-dehydro-derivative (I) of the compounds which are going to be subjected to such introduction.

REACTION DIAGRAM I in which the equations A, X, Y and CN have the meaning described hereinbefore and E is a member of the group consisting of hydrogen and methyl.

If the resulting A -7-cyano compound (lI)belongs to the IO-methyl series (IIA), it can subsequently be dehydrogenated at C-1 to produce the respective 7-cyano-1,4- dienes (III).

For preparing the starting 6-dehydro compounds we applied methods Which have already been described; in the compounds of the ld-methyl series we introduced the double bond at C-6,7 by refluxing with ohloranil in mixture with xylene (cf. Agnello and Laubach, J. Am. Chem. Soc, 79, 1257 (1957)) or in mixture with ethyl acetate and acetic acid; in the 19-nor-A -3-ketones we introduced the double bond at C-6,7 by formation of their 3-enol-ethers followed by reaction with hvnobromous acid and dehydroaoeaeea bromination of the resulting 6,13-bromo-19-nor-Af-3-ketones (of. Bowers, Casas, Zderic and Djerassi, patent application Serial No. 806,763, filed on April 16, 1959).

As described in the latter patent application, a steroid starting compound having the general Formula IV in the Reaction Diagram II given below, in which E, R X, Y have the same meaning as explained hereinbefore,

REACTION DIAGRAM II OR OR Enol ether formation IV V lHO Br 0 R I X l X D h e ydro- 0 bromination I Br I VI is converted into its 3-ethy1-enol-ether (V), which is treated with hypobromous acid to produce the known 6;?- bromo-testosterone acetate or 6,6-bromo-l9-nor-testosterone acetate (VI). The enol-ether is produced by known methods, for example by reaction with ethyl orthoformate in mixture with ethanol and dioxane, under anhydrous conditions and in the presence of p-toluenesulfonic acid; the reaction with hypobromous acid can be eifected with any reagent capable of liberating such acid, such as a N-bromoimide or N-bromoamide, or the hypob-romite of an alkali metal or alkaline earth metal; preferably we employ N-bromo-succinimide in mixture with sodium acetate, acetic acid and acetone.

Intermediate VI is then dehydrobrominated to A- androstadien-17fi-ol-3-one l7-acetate, or its 19-nor-analog, respectively (I), for example by refluxing with calcium carbonate in mixture with dimethylformamide.

The starting compounds (I) prepared in the aforesaid manner were refluxed with an excess of potassium cyanide in 95% ethanol and thus we obtained a mixture of the respective cand 7fi-n -compounds; the isomers were separated by chromatography. For introducing an additional double bond at C-1 of the 7-cyano-A -compounds of the IO-methyl series, we refluxed them with selenium dioxide in mixture with t-butanol, in the presence of catalytic amounts of pyridine and under an atmosphere of nitrogen.

The C-17 hydroxyl group of all of the 7-cyano-17,B- hydroxy compounds, obtained by the method of the present invention, can be esterified by conventional methods with the radicals of any of the acids specified above.

To those skilled in the art it is obvious that our method can be modified Within wide limits. The introduction of the cyano group at C-7 implies the addition of the elements of hydrogen cyanide to the double bond at C-6,7 of the 6 dehydro compounds; therefore, there can be employed for this reaction instead of potassium cyanide any other reagent capable of generating hydrogen cyanide, such as the cyanide of another alkali or alkali-earth metal; the ethanol may be substituted by another hydroxylated solvent, such as methanol or mixtures of methanol or ethanol and Water. We also applied microbiological methods for the dehydrogenation at C-1, such as incubation with Corynebacterium simplex ATCC 6946, and the like.

The invention will be further illustrated by a number of examples without being thereby limited in its scope.

Example I A mixture of 5 g. of G-dehydro-testosterone prepared as described by Sondheimer et a1. in IACS 75, 5932, et seq. (1953), 10 g. of potassium cyanide and 250* cc. of ethanol was refluxed for 2 /2 hours, cooled, diluted with water and the reaction product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. By chromatography of the residue on neutral alumina there were isolated 7oc-CYE1I10-IESIOSI6IOI16 and 7,8-cyano-testosterone.

Example 11 Example I is repeated with 6-dehydro-l7a-methyl-testosterone, prepared by dehydrogenation of Nix-methyltestosterone with chloranil, by using the method described in Patent No. 2,836,607, Example I, thus yielding 17ccmethyl-7a-cyano-testosterone and 17a-methyl-7/3-cyano testosterone.

The method of the preceding examples was applied to the compounds cited under I in the following table to prepare the end products listed under II:

Ex. I II N 0. Starting material Source of starting compound Final products 111.... 17a-ethyl-fi-dehydro-testos- U.S. Patent 2,739,974 7a-and 7fi-eyano-17a-ethy1- terone. testosterone.

IV 17a-vmyl-d-dehydro-testos- Prepared from l7a-vinyltestosterone by the method of dehydrogenation de- 70: and 7fl-cyano-17a-vinylterone. scribed in Patent 2,836,607. testosterone.

V 17a-propyn-(D-yl-6-dehy- Prepared from l7a-propyn-(l)-y1-testosterone (J. Pharm. Pharmacol, 1957, 929) 7aand 7fi-cyano-17a-propyndro-testosterone. by the dehydrogenation method of Patent 2,836,607. (1)-yl-testosterone.

VI 17a-ethynyl-6-dehydro Prepared from 17a-ethynyltestosterone by the method of dehydrogenation de- 7aand 7fl-cyan0-17a-ethyntestosterone. scribed in Patent 2,836,607. yl-testosterone.

VII-.- l7a-propen-(1)-yl-6-dehy- Prepared from 17a-propyn-(1)-yl testerone by hydrogenation to 17a-propen-(1)- 7aand 7fl-cyano-l7a-propen- (ire-testosterone. yl-testosterone by the method described in J. Am. Chem. Soc. 77, 148 (1955) (1)-yl-testosterone,

by Sandoval et a1. and dehydrogenation of the latter compound by the method of Patent 2,836,607.

VIIL- A ;androstadiene-3,17- Romo et al J. Org. Chem. 16, 1873 (1951) 7aand 7B-oyano-A -nndrodrone. stene-3,17-dione.

IX G-dehydro-llB-hydroxy- Prepared from llfi-hydroxy-testosterone by the dehydrogenation method de- 7aand 7fi-cyano-ll6-hytestosterone. scribed in Patent 2,836,607. droxy-testosterone.

X fi-dehydro-17a-methyl-11B- Prepared from 17a-methyl-11B-hydroxytestosterone (Patent 2,638,533) by the 711- and 7B-cyano-17lz-methylhydroxy-testosterone. method of Patent 2,836,607. 1lfi-hydroxy-testosterone.

XI 6-dehydro-17a-ethyl-llfl- Prepared from 17a-ethyhtestosterone by incubation with adrenal glands as de- 704- and 7fi-cyano-l7a-ethylhydroxy-testosterone. ipribed zng3gggnt 2,781,292 followed by dehydrogenation by the method of llfl-hydroxy-testosterone.

a en

XII- 19-nor-A}, -androstadiene- Prepared from 19-nor-A -androstene-3,17-dione by the dehydrogenation method 711- and 7B-cyano-l9-nor-A 3,17-d10ne. described in Patent 2,836,607. androstene-3,17-dione.

XIII 6-dehydro-17a-ethynyl-19- Prepared from l7a-ethynyl-19-n0r-testosterone by the dehydrogenation method 7aand 'ifi-cyano-lm-ethnylnor-testosterone. described in Patent 2,836,607. IQ-nor-testosterone.

XIV G-dehydro-lQmor-llfi-hy- Patent 2,864,830-- 7aand 7B-cyano-19-nor-1lfldroxy-testosterone. hydroxy-testosterone.

Example XV To a solution of 4.73 .g. of 19-nor-testosterone in 24 cc. of anhydrous dioxane there was added 5 cc. of ethyl orthoformate and then 0.64 g. of a solution of 500 mg. of p-toluene-sulfonic acid monohydrate in 5.4 cc. of dioxane and 1.1 cc. of absolute ethanol; the mixture was kept at room temperature for 1 hour, the solvent was evaporated under reduced pressure and the residue was crystallized from methanol. There was thus obtained 3-ethoxy- 19-nor-A -androstadiend73-01.

A solution of 1.73 g. of the above compound in 140 cc. of acetone was cooled to 5 C. and treated With 10.4 cc. of water and 1.04 g. of anhydrous sodium acetate; the mixture was then treated with stirring with 1.33 g. of N-bromosuccinimide and 1.04 cc. of glacial acetic acid and then stirred for 1 hour at a temperature around 5 C. After diluting with water, the product was extracted with benzene and the extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue consisted of the crude 6fi-bromo-19-nor-testosterone which was used for the next step without further purification. In another experiment the pure compound was obtained by recrystallization from ether.

The above crude acetate was mixed with 3.2 g. of calcium carbonate and 40 cc. of dimethylformamide and refluxed under an atmosphere of nitrogen for 1 hour; the mixture was cooled, filtered and the filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. The residue was chromatographed on neutral alumina and the solid fractions were recrystallized from acetone. There was thus obtained 19-nor-A -androstadien-17-ol-3-one.

This latter compound was treated with potassium cyanide in ethanol, exactly as described in Example I. There were thus obtained 7a-cy'ano-l9 nor-testosterone and 7;8-cyano-l9-nor-testosterone.

The method of the latter example was applied to the compounds cited under I in the following table, to prepare the 7aand 7B-cyano derivatives hsted below under II.

Ex. Starting material Source of starting Final products compound XVI..- 19-nor-17a-methy1 Known 7aand 7B-cyano-19- testosterone. nor-17a-methyl testosterone.

XVII. 19-nor-17a-vinyl- A. Sandovalet a1., 7aand 7fl-cyano-19- testosterone. J. Am. Chem. nor-17a-vinyl- 800., 77, 148 testosterone. (1955).

XV'III. 19-nor-11fl- Patent 2,702,811." 704- and 7 8-cyano-19- hydroxy-17anor-llfi-hydroxyvinyltestos- Nor-vinylterone. testosterone.

XIX. 19-nor-17a-ethy1- Known eom- 7aand 7fl-eyano-l9- testosterone. pound. nor-17a-ethyltestosterone.

Example XX -By treating G-dehydro-19-nor-17a-propyn-(1)-yl-testosterone according to the procedure described in Example I there are obtained the 70cand 7fi-cyano derivatives of 19-nor-17a-propyn-( 1 -yl testosterone.

The starting compound is prepared from l9-nor-A -androstene-3,17-dione by treatment with propyne-(l) following the method described by Ruzicka et al. in Helv. Chim. Acta 20, 1280 (1937), followed by the dehydrogenation with chloranil, described in Patent 2,836,607, Example I.

Example XXI By following the same procedure of Example I with 6 dehydro-9a-fluoro-l lB-hydroxy-l7a-methyl-19-nor-testosterone there were obtained 7a-cyano-9u-fluoro-1lfi-hydroxy-17a-methy1-19-nor-testo-sterone and 7fl-cyano-9ocfluoro-llfl-hydroxy-lh-methyl-l9-nor-testosterone. The starting material was obtained from 17a-methyl-9a-fluoro- 6 11fl-hydroxy-19-nor-testosterone (US. Patent 2,793,218) by the dehydrogenation method of Patent 2,836,607;

Example XXII Example I was repeated with 6-dehydro-17a-ethynyl- 1la-hydroxy-9a-fiuoro-m nor-testosterone, obtained from l:1fi-hydroxy-l9-nor-testosterone (US. Patent 2,655,518) by the method of Fried et al. (US Patent 2,852,511) followed by dehydrogenation with chloranil by the method of Patent 2,836,607, affording finally 7a-cyano-17a-ethyny-l- 1lfi-hydroxy-9a-fluoro-19-nor-testosterone and 7,8-cyano- 17a-ethinyl-1 1B-hyd-roxy-9a-fluoro-19-nor-testosterone.

Example XXIII Example I was repeated with 6-dehydro-17a-vinyl-11fihydroxy-9a-fluoro-19-nor-testosterone, disclosed in US. Patent 2,836,607, yielding 7u-cyano-l7a-vinyl-1lfi-hydroxy-9a-fluoro-l9-nor-testosterone and 7, 8cyano-l7avinyl-1 1,8-hydroxy-9a-fluoro-19-nor-testosterone.

Example XXIV A mixture of 2 g. of 7a-cyano-testosterone, obtained as described in Example I, cc. of t-butanol, 1.2 g. of selenium dioxide and 0.5 cc. of pyridine was refluxed for 48 hours. It was then filtered through celite, the solvent was removed under reduced pressure and the residue was decolorized with charcoal by refluxing its acetone solue tion for 1 hour. The solvent was evaporated and the residue was purified by chromatography on neutral alumina, thus giving 7a-cyano-l-dehydro-testosterone.

A mixture of 1 g. of the above compound, 5 cc. of pyridine and 1 cc. of acetic anhydride was kept overnight at room temperature. It was then poured into water, heated for half an hour on the steam bath, cooled and the precipitate was collected by filtration, washed with water, dried and recrystallized from acetone-hexane, thus yielding 7a-cyano-l-dehydro-testosterone acetate.

Example XXV By treating 7a-cyano-1lfi-hydroxy-19-nor-testosterone, obtained as described in Example XIV, according to the second step of the method of the previous example, but substituting the acetic anhydride by propionic anhydride, there was obtained 7a-cyano-11fi-hydroxy-19-nor-testosterone 17-propionate.

Example XXVI By the reaction with selenium dioxide (see Example XXIV), 1 g. of 17a-ethynyl-7a-cyano-testosterone (Example VI) was converted into 17a-ethynyl-7a-cyarro-1- dehydro-testosterone. A mixture of 500 mg. of the latter, 5 cc. of pyridine and 2 cc. of cyclopentylpropionic anhydride was heated for 24 hours at a temperature around 9 0 C. and poured into water, heated for half an hour on the steam bath and cooled; the product was ex tracted with methylene chloride and the extract was washed to neutral, dried over anhydrous sodium sulfate and the solvent was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 17aethynyl-7a-cyano-l-dehydro-testosterone 17-cyclopentylpropionate.

Example XX VII A solution of 2 g. of 17a-methyl-7acyano-9a-fluoro- 1lp-hydroxy-l9-nor-testosterone (Example XXI) in 100 cc. of benzene was treated with 5 g. of benzoic anhydride and 300 mg. of p-toluenesulfonic acid and kept at room temperature for 48 hours. After diluting with water the benzene layer was separated, washed with water and evaporated to dryness. The residue was treated with 100 cc. of a 1% methanolic solution of potassium hydroxide and kept for 1 hour at 0 C. under an atmosphere of nitrogen. The mixture was acidified with acetic acid, concentrated to a small volume and diluted with water; the product was extracted with methylene chloride and the extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. By recrystallization of the residue from acetone-hexane there was obtained 17OL-l'l16thY1-70c-CYE1HO-9ot-flUOI'O-1I a-hydroxy-19-nor-testosterone 17-benzoate.

Example XX VIII 1 g. of 7a-cyano-17a-methyl-9u-fluoro-11fl-hydroxy-19- nor-testosterone, obtained in Example XXI, was treated with 0.6 g. of selenium dioxide and 0.25 cc. of pyridine, exactly as described in Example XXIV; after chromatography on neutral alumina, 7a-cyano-l7ot-methyl-9afiuoro-l-l 3hydroxy-l-dehydrotestosterone was obtained.

Example XXIX 1 gram of 7,8-cyano-1lfl-hydroxy-testosterone obtained according to Example IX, is converted to the 17-acetate by a conventional method of 'acetylation, and to the resulting ester there is added an S-Normal solution of chromic acid in acetone and a small amount of sulfuric acid; the resulting 7fi-cyano-1l-keto-testosterone l7-acetate is isolated by chromatography in a well-known manner, and the acetate is then conventionally saponified, so that 7fi-cyano-1l-keto-testosterone is obtained.

Example XXX in which A is an arrangement selected from the group consisting of OH CH =0 OH 0R1 and wherein R is an acyl radical derived from a hydrocarbon carboxylic acid having up to 12 carbon atoms and R is an aliphatic hydrocarbon radical selected from the group of lower alkyl, alkenyl and alkynyl radicals; Y is an arrangement selected from the group consisting of H OH 4 and =0; X is hydrogen when Y is and is selected from the group consisting of hydrogen and fluorine, when Y is one of the other two members of its group, and -CN is selected from the group consisting of 7u-cy ano and 7,8-cyano.

2. A new steriod compound corresponding to the general formula in which A is an arrangement selected from the group consisting of '11 '11 'R "R wherein R is an acyl radical derived from a hydrocarbon carboxylic acid having up to 12 carbon atoms and R is an aliphatic hydrocarbon radical selected from the group of lower alkyl, alkenyl and alkynyl radicals; Y is an arrangement selected from the group consisting of OH OR.

and

and :0; X is hydrogen when Y is and is selected from the group consisting of hydrogen and fluorine, when Y is a member of its group other than and -CN is selected from the group consisting of 7ot-cy ano and 7,8-cyano.

3. 7-cyano-testosterone. 4. 17a-rnethyl-7-cyano-testosterone. 5. 7-cyano-17u-ethyltestosterone. 6. 7-cyano-17a-vinyltestosterone. 7. 7-cyano-l7a-propen-(l)yl-testosterone. 8. 7-cyano-17x=ethynyltestosterone 9 7-cyano-17u-propyn-( 1)yl-testosterone.

7-cyano-1lfi-hydroxytestosterone. 7-cyano-l7a-methyl-11 ,B-hydroxytestosterone. 7-cyano-l7ot-ethynyl-19-nor-testosterone. 7-cyano-19-nor-1lp-hydroxytestosterone 7-cyano-19-nor-testosterone. 7-cyano-19-nor-17a-methyltestosterone. 7-cyano-19-nor-1lp-hydroxy-17a-vinyltestosterone. 7-cyano-l-dehydrotestosterone. 18. 7 'cyano l7a-methyl-9ot-fluono-llfi-hydroxy-h dehydrotestosterone.

19. 7-cyano-1l-keto-testosterone. 20. A new steroid compound corresponding to the general formula:

I X CH3 u' 0- NW 0N in which A is an arrangement selected from the group consisting of =0 and wherein R is an acyl radical derived fnorn a hydrocarbon carboxylic acid having up to 12 carbon atoms and R is an aliphatic hydrocarbon radical selected from the 1 0 group of lower alkyl, alkenyl and alkynyl radicals; Y is and fluorine, when Y is a member of its group other than an arrangement selected from the group consisting of H H OH K i K H H H 5 and -CN is selected from the group consisting of 7aand :0; X is hydrogen when Y is cyano and 7B-cyano.

References Cited in the file of this patent Bowers et al.: Journal of American Chemical Society 10 and is selected from the group consisting of hydrogen (81) 1959 5233' 

1. A NEW STEROID COMPOUND CORRESPONDING TO THE GENERAL FORMULA: 